OCT and OCT-A biomarkers in multiple sclerosis - review

Objective: Retinal neuronal and vascular changes have been observed in multiple sclerosis (MS) patients. The aim of this review was to highlight the most current optical coherence tomography (OCT) and optical coherence tomography angiography (OCT-A) data in MS and to provide information about the possibility of using OCT / OCT-A parameters as biomarkers for screening, diagnosis and monitoring of MS. Methods: To carry out this review, a meticulous literature search was undergone on PubMed between 2014 and the present day, using the following terms: “multiple”, “sclerosis”, “optical”, “coherence”, “tomography” and “angiography”. Additional studies were found via references, being chosen according to relevance. Results: Retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) were significantly lower in MS patients compared to controls, and correlated with clinical and paraclinical variables, such as visual function, disability, and magnetic resonance imaging (MRI). Retinal capillary plexuses could be higher, lower or the same, and the best OCT-A microvasculature parameter for the detection of MS was the superficial capillary plexus (SCP). The reduced retinal vessel density (VD) was correlated with the disability in MS. Conclusions: OCT and OCT-A parameters could improve the development of retinal biomarkers for screening, early diagnosis and monitoring the disease progression of MS, and they could improve the development of potential future therapies that could slow or stop the course of this incurable disease. Abbreviations: DCP = deep capillary plexus; EDSS = Expanded Disability Status Scale; GCC = ganglion cell complex; GCL = ganglion cell layer; MRI = magnetic resonance imaging; MS = Multiple sclerosis; OCT = optical coherence tomography; OCT-A = optical coherence tomography angiography; ON = optic neuritis; RNFL = retinal nerve fiber layer; SCP = superficial capillary plexus; VD = vessel density


Introduction
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that typically presents in young people [1]. Considering the eye as the brain's window [2] and given the optically accessible eye, the structural and vascular changes in the retina may act as a surrogate for the brain changes in MS [3].
Optical coherence tomography (OCT) is a noninvasive reproducible method that has significantly developed over the past 20 years [4,5]. The OCT technology is comparable to that of the ultrasound, but it requires infrared light to analyze the backscattering of retinal tissues [5]. Using patterns of infrared reflection, OCT allows a precise quantification of the retinal layers, such as retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) [5]. One of the most significant pathogenic components that leads to persistent disability in MS is neurodegeneration and OCT has proven to be a sensitive and useful alternative to magnetic resonance imaging (MRI) for the investigation of this process [5].
Optical coherence tomography angiography (OCT-A) is a new diagnostic tool, which was commercially introduced in 2014 [6] and may provide the chance to evaluate modifications in cerebral vasculature by looking at retinal vasculature [2]. OCT-A makes it possible to see the retinal capillary layers and choroidal vascular network in vivo [7].
The application of OCT and OCT-A in MS is still unclear, but it seems promising [8]. Given the difficulty of MS diagnosis, which is based on an expensive and time-consuming method, there is a substantial interest to utilize the OCT and OCT-A parameters as low-cost biomarkers for screening, diagnosis and monitoring of MS [9].

Methods
To carry out this review, a meticulous literature search was undergone on PubMed using the following terms: "multiple", "sclerosis", "optical", "coherence", "tomography" and "angiography". The inclusion criteria were: articles that mentioned the terms above and studies that were performed between 2014 and the present day, after the commercially introduction of OCT-A [6].
Additional studies were found via references, and were chosen based on relevance.

Results
According to current literature, it is well known that MS has statistically significant reductions in the thickness of the RNFL and the GCL [8,10,11], even in the absence of prior optic neuritis (ON) [12]. A newly compensated peripapillary RNFL thickness for ocular anatomical parameters suggested a smaller interindividual variability, so it was the best neuronal parameter for the detection of MS, followed by ganglion cell complex (GCC, combining RNFL + GCL + inner plexiform layer) from the macular area [13]. Furthermore, OCT scans have been linked to progressive retinal and brain atrophy [14,15]. According to a cohort research, monitoring peripapillary RNFL is crucial to predict the five-year risk of disability worsening in patients with MS [14,16]. Reduced retinal thickness has a correlation with clinical and paraclinical variables, such as visual function and MRI [4], and it is inversely correlated with the disease duration [8] and disability [14].
There are only a few OCT-A studies, but with heterogeneous results. In most studies, it was found that the vessel density (VD) in the superficial capillary plexus (SCP) in MS eyes is decreased compared to controls [17,18]. It can also be unaffected [19] or even increased, but only in MS patients without history of ON [11,20]. Regarding deep capillary plexus (DCP) in MS eyes, it can be decreased [20,21], unaffected [22], or increased [11] compared to controls. Regarding choroidal vascular network, it can be unaffected [20] or increased for MS patients without history of ON [23]. The causes of these OCT-A inconsistencies are unclear, however they might be linked to the selection of study population, such as including the different MS subtypes with or without history of ON, OCT-A data interpretation or maybe they are different stages in the pathophysiology of this disease. It is reported that the best OCT-A microvasculature parameter for the detection of MS is the SCP [20]. OCT-A can detect even the subclinical vascular changes [17], and the reduced retinal VD is correlated with Expanded Disability Status Scale (EDSS) [10], resulting that OCT-A parameters could be promising biomarkers for screening, diagnosis and monitoring of MS [10,17].
The detection of neurodegenerative changes using OCT and the detection of microvascular changes using OCT-A have allowed scientists to understand more about the pathophysiology of MS, but they have generally focused on using either structural thickness [24,25] or vascular characteristics [17,19] alone. Therefore, there is a lack of information on the combined impact of OCT and OCT-A parameters as potential biomarkers in MS.

Conclusion
Using both structural and vascular characteristics could improve the diagnostic performance of MS and the risk prediction for disease progression in MS. However, validation studies are needed to establish that the OCT and OCT-A parameters could be used for the development of retinal biomarkers for screening, early diagnosis and monitoring the disease progression of MS, and for the development of potential future therapies that could slow or stop the course of this incurable disease. The aim of this literature review was to highlight the most current OCT and OCT-A data in MS and to serve as a resource for future studies.